The invention relates to novel substituted benzimidazoles, a process for their preparation, and use thereof as pharmaceuticals.
The application WO 94/12478 describes, inter alia, benzimidazole derivatives that inhibit blood platelet aggregation.
NFxcexaB is a heterodimeric transcription factor that can activate a large number of genes that code, inter alia, for proinflammatory cytokines such as IL-1, IL-2, TNFxcex1, or IL-6. NFxcexaB is present in the cytosol of cells, complexed with its naturally occurring inhibitor IxcexaB. The stimulation of cells, for example, by cytokines, leads to the phosphorylation and subsequent proteolytic degradation of IxcexaB. This proteolytic degradation leads to the activation of NFxcexaB, which subsequently migrates into the nucleus of the cell and there activates a large number of proinflammatory genes.
In disorders such as rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer""s disease, or atherosclerosis, NFxcexaB is activated beyond the normal extent. The inhibition of NFxcexaB is also of benefit in cancer therapy, since it is employed there for the reinforcement of the cytostatic therapy. It was possible to show that pharmaceuticals such as glucocorticoids, salicylates, or gold salts, which are employed in rheumatic therapy, intervene in an inhibitory manner at various points in the NFxcexaB-activating signal chain or interfere directly with the transcription of the genes.
The first step in the signal cascade mentioned is the degradation of IxcexaB. This phosphorylation is regulated by the specific IxcexaB kinase. To date, no inhibitors are known which specifically inhibit IxcexaB kinase.
In the attempt to obtain active compounds for the treatment of rheumatoid arthritis (in the case of inflammation), osteoarthritis, asthma, cardiac infarct, Alzheimer""s disease, carcinomatous disorders (potentiation of cytotoxic therapies), or atherosclerosis, it has now been found that the benzimidazoles according to the invention are strong and very specific inhibitors of IxcexaB kinase.
The invention therefore relates to compounds of formula I 
or a stereoisomeric form of the compound of formula I or a physiologically tolerable salt of the compound of formula I, where one of the substituents R1, R2, R3, and R4 is a radical of formula II 
in which:
D is xe2x80x94C(O)xe2x80x94, xe2x80x94S(O)xe2x80x94, or xe2x80x94S(O)2xe2x80x94;
R8 is hydrogen or (C1-C4)-alkyl;
R9 is
(1) a characteristic radical of an amino acid;
(2) aryl, in which aryl is unsubstituted or substituted;
(3) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
(5)(1) aryl, in which aryl is unsubstituted or substituted;
(5)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(5)(4) xe2x80x94Oxe2x80x94R11;
(5)(5) xe2x95x90O;
(5)(6) halogen;
(5)(7) xe2x80x94CN;
(5)(8) xe2x80x94CF3;
(5)(9) xe2x80x94S(O)xxe2x80x94R11, in which x is the integer 0, 1, or 2;
(5)(10) xe2x80x94C(O)xe2x80x94Oxe2x80x94R11;
(5)(11) xe2x80x94C(O)xe2x80x94N(R11)2;
(5)(12) xe2x80x94N(R11)2;
(5)(13) (C3-C6)-cycloalkyl; 
(5)(14) a radical of formula
xe2x80x83or
(5)(15) a radical of formula 
xe2x80x83in which
R11 is
(a) hydrogen;
(b) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by
xe2x80x83(1) aryl, in which aryl is unsubstituted or substituted;
xe2x80x83(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
xe2x80x83(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
xe2x80x83(4) halogen;
xe2x80x83(5) xe2x80x94Nxe2x80x94(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by xe2x80x94COOH;
xe2x80x83(6) xe2x80x94Oxe2x80x94(C1-C6)-alkyl; or
xe2x80x83(7) xe2x80x94COOH;
(c) aryl, in which aryl is unsubstituted or substituted;
(d) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; or
(e) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted; and
in the case of (R11)2, R11 independently of one another has the meaning of (a) to (e);
Z is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4) xe2x80x94(C1-C6)-alkyl, in which alkyl is substituted or unsubstituted independently of one another by
(4)(1) aryl, in which aryl is unsubstituted or substituted;
(4)(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(4)(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(4)(4) halogen;
(4)(5) xe2x80x94Nxe2x80x94(C1-C6)n-alkyl, in which n is the integer 0, 1, or 2, and alkyl is unsubstituted or mono-, di-, or trisubstituted independently of one another by halogen or by xe2x80x94COOH;
(4)(6) xe2x80x94Oxe2x80x94(C1-C6)-alkyl; or
(4)(7) xe2x80x94COOH; or
(5) xe2x80x94C(O)xe2x80x94R10, in which
R10 is
(1) xe2x80x94Oxe2x80x94R11; or
(2) xe2x80x94N(R11)2;
in which R11 is as defined above; or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a heterocyclic ring of formula IIa 
xe2x80x83in which:
D, Z, and R10 are as defined in formula II;
A is nitrogen or xe2x80x94CH2xe2x80x94;
B is oxygen, sulfur, nitrogen, or xe2x80x94CH2xe2x80x94;
X is oxygen, sulfur, nitrogen, or xe2x80x94CH2xe2x80x94;
Y is absent or is oxygen, sulfur, nitrogen, or xe2x80x94CH2xe2x80x94; or
X and Y together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, A, X, Y, B, and the carbon contains no more than one oxygen; X is not oxygen, sulfur, or nitrogen if A is nitrogen; contains no more than one sulfur; contains 1, 2, 3, or 4 nitrogens; and where oxygen and sulfur do not occur at the same time;
where the ring system formed by N, A, X, Y, B, and the carbon is unsubstituted or mono-, di-, or trisubstituted independently of one another by (C1-C8)-alkyl, in which alkyl is straight-chain or branched and is unsubstituted or mono- or disubstituted by
(1)(1) xe2x80x94OH;
(1)(2) (C1-C8)-alkoxy, in which alkoxy is straight-chain or branched;
(1)(3) halogen;
(1)(4) xe2x80x94NO2;
(1)(5) xe2x80x94NH2;
(1)(6) xe2x80x94CF3;
(1)(7) xe2x80x94OH;
(1)(8) methylenedioxy;
(1)(9) xe2x80x94C(O)xe2x80x94CH3;
(1)(10) xe2x80x94CH(O);
(1)(11) xe2x80x94CN;
(1)(12) xe2x80x94COOH;
(1)(13) xe2x80x94C(O)xe2x80x94NH2;
(1)(14) (C1-C4)-alkoxycarbonyl, in which alkoxycarbonyl is straight-chain or branched;
(1)(15) phenyl;
(1)(16) phenoxy;
(1)(17) benzyl;
(1)(18) benzyloxy; or
(1)(19) tetrazolyl; or
R9 and Z together with the carbons to which they each are bonded form a heterocyclic ring of formula IIc 
xe2x80x83in which:
D, R8, and R11 are as defined in formula II;
T is oxygen, sulfur, nitrogen, or xe2x80x94CH2xe2x80x94;
W is oxygen, sulfur, nitrogen, or xe2x80x94CH2xe2x80x94;
V is absent or is oxygen, sulfur, nitrogen, or xe2x80x94CH2xe2x80x94; or
T and V together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical; or
V and W together form a phenyl, 1,2-diazine, 1,3-diazine, or a 1,4-diazine radical;
where the ring system formed by N, T, V, W, and the two carbons contains no more than one oxygen, no more than one sulfur, and 1, 2, 3, or 4 nitrogen; where oxygen and sulfur do not occur at the same time; and where the ring system formed by N, T, V, W, and the two carbons is unsubstituted or mono-, di-, or trisubstituted independently of one another by the substituents defined above under (1)(1) to (1)(19); and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted;
(5) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted;
(6) (C1-C6)-alkyl;
(7) xe2x80x94CN;
(8) xe2x80x94NO2;
(9) xe2x80x94Oxe2x80x94(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(10) xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
(11) xe2x80x94OR11;
(12) xe2x80x94N(R11)2;
(13) xe2x80x94S(O)xxe2x80x94R11, in which x is the integer 0, 1, or 2; or
(14) xe2x80x94CF3;
in which R11 is as defined above;
R5 is
(1) hydrogen;
(2) xe2x80x94OH; or
(3) xe2x95x90O; and
R6 is
(1) aryl, in which aryl is unsubstituted or substituted;
(2) phenyl, mono- or disubstituted independently of one another by
(2)(1) xe2x80x94CN;
(2)(2) xe2x80x94NO2;
(2)(3) xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
(2)(4) xe2x80x94N(R11)2;
(2)(5) xe2x80x94NHxe2x80x94C(O)xe2x80x94R11;
(2)(6) xe2x80x94S(O)xxe2x80x94R11, in which x is the integer 0, 1, or 2;
(2)(7) xe2x80x94C(O)xe2x80x94R11; or
(2)(8) xe2x80x94(C1-C4)-alkylxe2x80x94NH2;
in which R11 is as defined above;
(3) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or substituted; or
(4) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or substituted.
A preferred compound of formula I is one where one of the substituents R1, R2, R3, and R4 is a radical of formula II in which
R8 is hydrogen;
R9 is
(1) a characteristic radical of an amino acid; or
(2) (C1-C6)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted independently of one another by at least one radical selected from pyrrole, pyrrole mono- or disubstituted independently of one another by xe2x80x94(C1-C4)-alkyl, pyrazole, phenyl, imidazole, triazole, thiophene, thiazole, oxazole, isoxazole, pyridine, pyrimidine, indole, benzothiophene, benzimidazole, benzoxazole, benzothiazole, azetidine, pyrroline, pyrrolidine, piperidine, isothiazole, diazepine, thiomorpholine, xe2x80x94CN, morpholine, azepine, pyrazine, 1,3,4-oxadiazole, xe2x80x94N(R13)-phenyl, wherein R13 is defined below, (C3-C6)-cycloalkyl, xe2x80x94OR11, xe2x80x94NH(R11), in which R11 is as defined above, xe2x80x94S(O)xxe2x80x94R12, in which x is the integer 0, 1, or 2, and R12 is naphthyl, pyrimidinyl, morpholinyl, or phenyl, which are unsubstituted or mono- or disubstituted independently of one another by xe2x80x94OH, (C1-C4)-alkyl, xe2x80x94CF3, halogen, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94COOH, xe2x80x94C(O)xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94NH2, or xe2x80x94NHxe2x80x94C(O)xe2x80x94(C1-C4)-alkyl, or C(O)xe2x80x94R12, in which R12 is as defined above;
Z is xe2x80x94C(O)xe2x80x94R10, tetrazole, (C1-C6)-alkyl, in which alkyl is unsubstituted or mono- or disubstituted independently of one another by phenyl or xe2x80x94OH, or 1,3,4-oxadiazole, in which 1,3,4-oxadiazole is unsubstituted or monosubstituted by
xe2x80x94NH2, xe2x80x94NH(C1-C4)-alkyl, xe2x80x94Nxe2x80x94[(C1-C4)-alkyl]2, xe2x80x94NHxe2x80x94C(O)xe2x80x94(C1-C4)-alkyl, xe2x80x94NHxe2x80x94C(O)xe2x80x94NHxe2x80x94(C1-C4)-alkyl, -NH-C(O)-NH-(C3-C7)-cycloalkyl, xe2x80x94NHxe2x80x94C(O)xe2x80x94NH-aryl, xe2x80x94NHxe2x80x94C(O)xe2x80x94NH-phenyl, xe2x80x94NHxe2x80x94SO2-aryl, xe2x80x94NHxe2x80x94SO2xe2x80x94(C1-C4)-alkyl, xe2x80x94OH, or xe2x80x94(C1-C4)-alkyl, in which R10 is xe2x80x94Oxe2x80x94R11, phenyl, pyrimidine, xe2x80x94OH, morpholinyl, xe2x80x94N(R11)2, or xe2x80x94NH2;
R11 is
(1) xe2x80x94(C1-C4)-alkyl;
(2) R13; or
(3) xe2x80x94N(R13)2, in which
R13 independently of one another is
xe2x80x83(a) hydrogen;
xe2x80x83(b) xe2x80x94(C1-C6)-alkyl;
xe2x80x83(c) xe2x80x94(C1-C4)-alkylxe2x80x94Oxe2x80x94(C1-C4)-alkyl;
xe2x80x83(d) xe2x80x94(C1-C6)-alkylxe2x80x94N(R13)2;
xe2x80x83(e) halogen; or
xe2x80x83(f) xe2x80x94(C0-C4)-alkyl, mono- or disubstituted by aryl, imidazolyl, morpholinyl, or phenyl; or
R8 and R9, together with the nitrogen and carbon to which they are each bonded, form a ring of formula IIa selected from pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolones, isoxazolones, triazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COOxe2x80x94(C1-C4)-alkyl, 3-hydroxypyrro-2,4-diones, 5-oxo-1,2,4-thiadiazoles, 1,3,4-oxadiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline, and isoquinoline; or
R9 and Z, together with the carbons to which they are each bonded, form a ring of formula IIc selected from pyrrole, pyrroline, pyrrolidine, pyridine, piperidine, piperylene, pyridazine, pyrimidine, pyrazine, piperazine, pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, imidazolidine, oxazole, isoxazole, 2-isoxazolidine, isoxazolidine, morpholine, isothiazole, thiazole, isothiazolidine, thiomorpholine, indazole, thiadiazole, benzimidazole, quinoline, triazole, phthalazine, quinazoline, quinoxaline, purine, pteridine, indole, tetrahydroquinoline, tetrahydroisoquinoline, isoquinoline, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, oxadiazolones, isoxazolones, triazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COOxe2x80x94(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 1,3,4-oxadiazole, and 5-oxo-1,2,4-thiadiazoles; and
the other substituents R1, R2, R3, and R4 are chosen independently of one another, and are
(1) hydrogen;
(2) halogen;
(3) (C1-C4)-alkyl;
(4) xe2x80x94CN;
(5) xe2x80x94NO2;
(6) xe2x80x94Oxe2x80x94(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(7) xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
(8) xe2x80x94Nxe2x80x94(C0-C4)-alkyl-aryl, in which alkyl is straight-chain or branched;
(9) xe2x80x94Nxe2x80x94(C1-C4)-alkyl; or
(10) xe2x80x94CF3;
R5is
(1) hydrogen;
(2) xe2x80x94OH; or
(3) xe2x95x90O; and
R6 is
(1) phenyl, mono- or disubstituted independently of one another by
(1)(1) xe2x80x94CN;
(1)(2) xe2x80x94NO2;
(1)(3) xe2x80x94Oxe2x80x94(C1-C4)-alkyl;
(1)(4) xe2x80x94NH2; or
(1)(5) xe2x80x94(C1-C4)-alkylxe2x80x94NH2;
(2) heteroaryl having 5 to 14 ring members, in which the heteroaryl is unsubstituted or mono-, di-, or trisubstituted independently of one another by xe2x80x94Nxe2x80x94R14, in which R14 is xe2x80x94(C1-C6)-alkyl, xe2x80x94(C3-C6)-cycloalkyl, phenyl, halogen, xe2x80x94OH, or xe2x80x94(C1-C4)-alkyl; or
(3) a heterocycle having 5 to 12 ring members, in which the heterocycle is unsubstituted or mono-, di-, or trisubstituted independently of one another by xe2x80x94Nxe2x80x94R14, in which R14 is xe2x80x94(C1-C6)-alkyl, xe2x80x94(C3-C6)-cycloalkyl, phenyl, halogen, -OH, or xe2x80x94(C1-C4)-alkyl.
The term xe2x80x9chalogenxe2x80x9d is understood as meaning fluorine, chlorine, bromine, or iodine. The term xe2x80x9c(C1-C4)-alkylxe2x80x9d is understood as meaning hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 4 carbon atoms. The term xe2x80x9c(C1-C6)-alkylxe2x80x9d is understood as meaning hydrocarbon radicals whose carbon chain is straight-chain or branched and contains 1 to 6 carbon atoms. The term xe2x80x9cCo-alkylxe2x80x9d is understood as meaning a covalent bond. Cyclic alkyl radicals are, for example, 3- to 6-membered monocyclic systems such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
The expression xe2x80x9cR8 and R9, together with the nitrogen atom and carbon atom to which they are each bonded, form a heterocyclic ring of formula IIaxe2x80x9d is understood as meaning radicals which are derived from pyrrole, pyrroline, pyrrolidine, imidazole, pyrazole, oxazole, tetrazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, 1,3,4-oxadiazole, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COOxe2x80x94(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, isoxazole, indole, isoxazoline, isoxazolidine, morpholine, thiazole, isothiazole, isothiazoline, purine, isothiazolidine, thiomorpholine, pyridine, piperidine, pyrazine, piperazine, pyrimidine, pyridazine, isoindole, indazole, benzimidazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, pteridine, imidazolidine, carboline, and benzo-fused derivatives of these heterocycles.
The term xe2x80x9carylxe2x80x9d is understood as meaning aromatic hydrocarbon radicals having 6 to 14 carbon atoms in the ring. (C6-C14)-Aryl radicals are, for example, phenyl, naphthyl, for example, 1-naphthyl, 2-naphthyl, biphenylyl, for example, 2-biphenylyl, 3-biphenylyl, and 4-biphenylyl, anthryl, or fluorenyl. Biphenylyl radicals, naphthyl radicals, and, in particular, phenyl radicals are preferred aryl radicals. Aryl radicals, in particular phenyl radicals, can be monosubstituted or polysubstituted, preferably monosubstituted, disubstituted, or trisubstituted, by identical or different radicals, preferably by radicals selected from (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, amino, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl such as hydroxymethyl, 1-hydroxyethyl, or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, or tetrazolyl. Further, when aryl is phenyl, phenyl is optionally mono- or disubstituted independently of one another by xe2x80x94CN, xe2x80x94NO2, xe2x80x94Oxe2x80x94(C1-C4)-alkyl, xe2x80x94N(R11)2, xe2x80x94NHxe2x80x94C(O)xe2x80x94R11, xe2x80x94S(O)xR1, in which x is the integer 0, 1, or 2, xe2x80x94C(O)xe2x80x94R11, in which R11 is as defined above, or xe2x80x94(C1-C4)-alkylxe2x80x94NH2. The same applies, for example, to radicals such as arylalkyl or arylcarbonyl. Arylalkyl radicals are, in particular, benzyl and also 1- and 2-naphthylmethyl, 2-, 3-, and 4-biphenylylmethyl, and 9-fluorenylmethyl. Substituted arylalkyl radicals are, for example, benzyl radicals and naphthylmethyl radicals substituted in the aryl moiety by one or more (C1-C8)-alkyl radicals, in particular (C1-C4)-alkyl radicals, for example, 2-, 3-, and 4-methylbenzyl, 4-isobutylbenzyl, 4-tert-butylbenzyl, 4-octylbenzyl, 3,5-dimethylbenzyl, pentamethylbenzyl, 2-, 3-, 4-, 5-, 6-, 7-, and 8-methyl-1-naphthylmethyl, 1-, 3-, 4-, 5-, 6-, 7-, and 8-methyl-2-naphthylmethyl, by one or more (C1-C8)-alkoxy radicals, in particular (C1-C4)-alkoxy radicals, benzyl radicals, and naphthylmethyl radicals substituted in the aryl moiety, for example, 4-methoxybenzyl, 4-neopentyloxybenzyl, 3,5-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 2,3,4-trimethoxybenzyl, nitrobenzyl radicals, for example, 2-, 3-, and 4-nitrobenzyl, halobenzyl radicals, for example, 2-, 3-, and 4-chloro- and 2-, 3-, and 4-fluorobenzyl, 3,4-dichlorobenzyl, pentafluorobenzyl, trifluoromethylbenzyl radicals, for example, 3- and 4-trifluoromethylbenzyl, or 3,5-bis(trifluoromethyl)benzyl.
In monosubstituted phenyl radicals, the substituent can be located in the 2-position, the 3-position, or the 4-position. Disubstituted phenyl can be substituted in the 2,3-position, the 2,4-position, the 2,5-position, the 2,6-position, the 3,4-position, or the 3,5-position. In trisubstituted phenyl radicals, the substituents can be located in the 2,3,4-position, the 2,3,5-position, the 2,4,5-position, the 2,4,6-position, the 2,3,6-position, or the 3,4,5-position.
The explanations for the aryl radicals apply accordingly to divalent arylene radicals, for example, to phenylene radicals that can be present, for example, as 1,4-phenylene or as 1,3-phenylene.
Phenylene-(C1-C6)-alkyl is in particular phenylenemethyl (xe2x80x94C6H4-CH2xe2x80x94) and phenyleneethyl. (C1-C6)-Alkylenephenyl is in particular methylenephenyl (xe2x80x94CH2-C6H4xe2x80x94). Phenylene-(C2-C6)-alkenyl is in particular phenyleneethenyl and phenylenepropenyl.
The expression xe2x80x9cheteroaryl having 5 to 14 ring membersxe2x80x9d represents a radical of a monocyclic or polycyclic aromatic system having 5 to 14 ring members, which contains 1, 2, 3, 4, or 5 heteroatoms as ring members. Examples of heteroatoms are N, O, and S. If a number of heteroatoms are contained, these can be identical or different. Heteroaryl radicals can likewise be monosubstituted or polysubstituted, preferably monosubstituted, disubstituted, or trisubstituted, by identical or different radicals selected from (C1-C8)-alkyl, in particular (C1-C4)-alkyl, (C1-C8)-alkoxy, in particular (C1-C4)-alkoxy, halogen, nitro, xe2x80x94N(R11)2, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl such as hydroxymethyl, 1-hydroxyethyl, or 2-hydroxyethyl, methylenedioxy, formyl, acetyl, cyano, hydroxycarbonyl, aminocarbonyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyl, benzyloxy, or tetrazolyl. Heteroaryl having 5 to 14 ring members preferably represents a monocyclic or bicyclic aromatic radical which contains 1, 2, 3, or 4, in particular 1, 2, or 3, identical or different heteroatoms selected from N, O, and S, and which can be substituted by 1, 2, 3, or 4, in particular 1, 2, or 3, identical or different substituents selected from (C1-C6)-alkyl, (C1-C6)-alkoxy, fluorine, chlorine, nitro, xe2x80x94N(R11)2, trifluoromethyl, hydroxyl, hydroxy-(C1-C4)-alkyl, (C1-C4)-alkoxycarbonyl, phenyl, phenoxy, benzyloxy, and benzyl. Heteroaryl particularly preferably represents a monocyclic or bicyclic aromatic radical having 5 to 10 ring members, in particular a 5-membered or 6-membered monocyclic aromatic radical which contains 1, 2, or 3, in particular 1 or 2, identical or different heteroatoms selected from N, O, and S, and can be substituted by 1 or 2 identical or different substituents selected from (C1-C4)-alkyl, halogen, hydroxyl, xe2x80x94N(R11)2, (C1-C4)-alkoxy, phenyl, phenoxy, benzyloxy, and benzyl. R11 is as defined in substituent R9 of formula I.
The expression xe2x80x9cheterocycle having 5 to 12 ring membersxe2x80x9d represents a monocyclic or bicyclic 5-membered to 12-membered heterocyclic ring that is partly saturated or completely saturated. Examples of heteroatoms are N, O, and S. The heterocycle is unsubstituted or substituted on one or more carbons or on one or more heteroatoms by identical or different substituents. These substituents have been defined above for the radical heteroaryl. In particular, the heterocyclic ring is monosubstituted or polysubstituted, for example, monosubstituted, disubstituted, trisubstituted, or tetrasubstituted, on carbons by identical or different radicals selected from (C1-C8)-alkyl, for example, (C1-C4)-alkyl, (C1-C8)-alkoxy, for example, (C1-C4)-alkoxy such as methoxy, phenyl-(C1-C4)-alkoxy, for example, benzyloxy, hydroxyl, oxo, halogen, nitro, amino, or trifluoromethyl, and/or it is substituted on the ring nitrogens in the heterocyclic ring by (C1-C8)-alkyl, for example, (C1-C4)-alkyl such as methyl or ethyl, by optionally substituted phenyl or phenyl-(C1-C4)-alkyl, for example, benzyl. Nitrogen heterocycles can also be present as N-oxides or as quaternary salts.
Examples of the expressions heteroaryl having 5 to 14 ring members or heterocycle having 5 to 12 ring members are radicals which are derived from pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, 1,3,4-oxadiazole, 1,2,3,5-oxathiadiazole-2-oxides, triazolones, oxadiazolones, isoxazolones, oxadiazolidinediones, triazoles which are substituted by F, CN, CF3, or COOxe2x80x94(C1-C4)-alkyl, 3-hydroxypyrrole-2,4-diones, 5-oxo-1,2,4-thiadiazoles, pyridine, pyrazine, pyrimidine, indole, isoindole, indazole, phthalazine, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, carboline, and benzo-fused, cyclopenta-, cyclohexa-, or cyclohepta-fused derivatives of these heterocycles. Particularly preferred radicals are 2- or 3-pyrrolyl, phenylpyrrolyl such as 4- or 5-phenyl-2-pyrrolyl, 2-furyl, 2-thienyl, 4-imidazolyl, methylimidazolyl, for example, 1-methyl-2-, 4-, or -5-imidazolyl, 1,3-thiazol-2-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3-, or 4-pyridyl-N-oxide, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 2-, 3-, or 5-indolyl, substituted 2-indolyl, for example, 1-methyl-, 5-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro-, or 4,5-dimethyl-2-indolyl, 1-benzyl-2- or -3-indolyl, 4,5,6,7-tetrahydro-2-indolyl, cyclohepta[b]-5-pyrrolyl, 2-, 3-, or 4-quinolyl, 1-, 3-, or 4-isoquinolyl, 1-oxo-1,2-dihydro-3-isoquinolyl, 2-quinoxalinyl, 2-benzofuranyl, 2-benzothienyl, 2-benzoxazolyl, or benzothiazolyl, or dihydropyridinyl, pyrrolidinyl, for example, 2- or 3-(N-methylpyrrolidinyl), piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrothienyl, or benzodioxolanyl.
The structural formula of xcex1-amino acids is as follows: 
The xcex1-amino acids differ from one another by the radical R, which in the context of the present application is described as a xe2x80x9ccharacteristic radicalxe2x80x9d of an amino acid.
In the case where R9 is the characteristic radical of an amino acid, the characteristic radicals employed are preferably those of the following naturally occurring xcex1-amino acids: glycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, histidine, arginine, glutamic acid, and aspartic acid. Those particularly preferred are histidine, tryptophan, serine, threonine, cysteine, methionine, asparagine, glutamine, lysine, arginine, glutamic acid, and aspartic acid. Preferred characteristic radicals of an amino acid which are furthermore employed as the radical R9 are also non-naturally occurring amino acids such as 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 2-aminopimelic acid, 2-amino-3-phenylaminoethyl-propionic acid, 2-amino-3-phenylamino-propionic acid, phenylglycine, 3-(2-thienyl)alanine, 3-(3-thienyl)alanine, 2-(2-thienyl)glycine, 2-aminoheptanoic acid, pipecolic acid, hydroxylysine, sarcosine, N-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, ornithine, allo-isoleucine, allo-threonine, allo-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, 3-(2-naphthyl)alanine, 3-(1-naphthylalanine), homophenylalanine, homocysteine, homocysteic acid, homotryptophan, cysteic acid, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, 3-(4-pyridyl)alanine, phosphinothricin, 4-fluorophenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, 3-fluorophenylalanine, 3-fluorophenylalanine, 2-fluorophenylalanine, 4-chlorophenylalanine, 4-nitrophenylalanine, 4-aminophenylalanine, cyclohexylalanine, citrulline, 5-fluorotryptophan, 5-methoxytryptophan, methionine sulfone, methionine sulfoxide, or xe2x80x94NHxe2x80x94NR11xe2x80x94CON(R11)2, which are optionally also substituted. In the case of natural but also of non-naturally occurring amino acids that have a functional group such as amino, hydroxyl, carboxyl, mercapto, guanidyl, imidazolyl, or indolyl, this group can also be protected.
Suitable protective groups for this are preferably the N-protective groups customarily used in peptide chemistry, for example, protective groups of the urethane type, benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenyloxycarbonyl (Fmoc), allyloxycarbonyl (Aloc), or of the acid amide type, in particular formyl, acetyl, or trifluoroacetyl, and of the alkyl type, for example, benzyl. In the case of an imidazole radical in R9, for example, the sulfonic acid derivative of formula IV employed for the sulfonamide formation is used as a protective group of the imidazole nitrogen, which can be removed again, in particular in the presence of bases such as sodium hydroxide solution.
The term xe2x80x9cindependently of one anotherxe2x80x9d is understood as meaning that the radicals selected are independent of one another and can be identical or different. For example, two radicals substituted independently of one another by A and B means that one radical may be A and the other may be B, both radicals may be A, or both radicals may be B.
The starting substances for the chemical reactions are known or can be easily prepared by methods known from the literature.
The invention further relates to a process for the preparation of compounds of formula I or a stereoisomeric form of compounds of formula I or of a physiologically tolerable salt of compounds of formula I, comprising
a) reacting a compound of formula IV 
xe2x80x83in which Pg is a suitable protective group (e.g., methyl ester), an amide group, or a hydroxyl group, and Z, R8, and R9 are as defined in formula II, with an acid chloride or an activated ester of the compound of formula III 
where D1 is xe2x80x94COOH or sulfonylhalogen, and R5 and R6 are as defined in formula I, in the presence of a base or, if appropriate, of a dehydrating agent in solution and, after removal of the protective group, converting into a compound of formula I, or
b) reacting a compound of formula IVa 
xe2x80x83in which R8 and R9 are as defined in formula II, and E is an N-amino protective group, with its carboxyl group coupled via an intermediate chain L to a polymeric resin of formula PS, a compound of formula V 
xe2x80x83resulting, which, after selective removal of the protective group E, is reacted with a compound of formula III, where R5 and R6 are as defined in formula I, in the presence of a base or, if appropriate, of a dehydrating agent to give a compound of formula VI 
xe2x80x83and converting the compound of formula VI, after removal of the support material, into a compound of formula I, or
c) reacting a compound of formula V, after selective removal of the protective group E, with a compound of formula VII 
xe2x80x83where D1 is xe2x80x94COOH or sulfonylhalogen, and RX is halogen and RY is a radical xe2x80x94NO2 or xe2x80x94NHxe2x80x94E, and E is a protective group, to give a compound of formula VIII 
xe2x80x83and then reacting the compound of formula VIII with a compound of formula IX
NH2xe2x80x94R6xe2x80x83xe2x80x83IX
xe2x80x83in which R6 is as defined in the compound of formula I, to give an intermediate compound of formula VIa 
xe2x80x83then either converting the intermediate compound of formula VIa into a compound of formula I after removal of the support material or reducing it, for example, with tributylphosphine, to give a compound of formula VI and converting into a compound of formula I after removal of the support material, or
d) converting a compound of formula I into a physiologically tolerable salt.
In process variant a) of the general working procedure, the acid functions of compounds of formula IVa are provided with a protective group Pg; this selective carboxylic acids derivatization is carried out according to methods such as are described in Houben-Weyl, Methoden der Org. Chemie (Methods of Organic Chemistry), Vol. 15/1. In process variant b) of the general working procedure, the amino functions of the starting compounds of formula IVa are provided with a protective group E; this selective amino groups derivatization is carried out according to methods such as are described in Houben-Weyl, Methoden der Org. Chemie (Methods of Organic Chemistry), Vol. 15/1.
A suitable protective group Pg preferably used for this is the carboxyl protective groups customary in peptide chemistry, for example, protective groups of the alkyl ester type, such as methyl, ethyl, tert-butyl, isopropyl, benzyl, fluorenylmethyl, or allyl, aryl ester type, such as phenyl, or amide type, such as amide or benzhydrylamine. Suitable protective groups E used for this are preferably the N-protective groups customary in peptide chemistry, for example, protective groups of the urethane type, such as benzyloxycarbonyl (Z), t-butoxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), and allyloxycarbonyl (Aloc), or of the acid amide type, in particular formyl, acetyl, or trifluoroacetyl of alkyl type such as benzyl.
The (trimethylsilyl)ethoxycarbonyl (Teoc) group has also proven particularly suitable for this (P. Kocixc3xanski, Protecting Groups, Thieme Verlag (1994)).
Starting materials used for the preparation of the benzimidazole derivatives of formula III are preferably 2,3- and 3,4-diaminobenzoic acids and aryl- or heteroarylaldehydes, which are reacted at 145xc2x0 C. in the presence of nitrobenzene as a solvent. The acids mentioned are furthermore reacted with methyl or ethyl imidates, which are prepared from the corresponding arylnitriles or heteroarylnitriles in a Pinner reaction.
For the condensation of compounds of formula IV with those of formula III, the coupling methods which are well-known per se to the person skilled in the art are advantageously used (see, for example, Houben-Weyl, Methoden der Org. Chemie (Methods of Organic Chemistry]), Vol. 15/1 and 15/2, Georg Thieme Verlag, Stuttgart (1974)). Suitable condensing agents or coupling reagents are compounds such as carbonyldiimidazole, carbodiimides such as dicyclohexylcarbodiimide or diisopropylcarbodiimide (DIC), O-((cyano(ethoxycarbonyl)methylene)amino)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate (TOTU), or propanephosphonic anhydride (PPA).
The condensations can be carried out under standard conditions. During the condensation, as a rule it is necessary for the non-reacting amino groups present to be protected by reversible protective groups. The same applies to carboxyl groups not involved in the reaction, which during the condensation are preferably present as (C1-C6)-alkyl esters, benzyl esters, or tert-butyl esters. Amino group protection is unnecessary if the amino groups are still present in the form of precursors such as nitro groups or cyano groups and are only formed by hydrogenation after the condensation. After the condensation, the protective groups present are removed in a suitable manner. For example, NO2 groups (guanidino protection in amino acids), benzyloxycarbonyl groups, and benzyl groups in benzyl esters can be removed by hydrogenation. The protective groups of the tert-butyl type are removed using acid, while the 9-fluorenylmethoxycarbonyl radical is removed by secondary amines.
The polymeric support designated in formulae V and VI by PS is a crosslinked polystyrene resin having a linker designated as the intermediate chain L. This linker carries a suitable functional group, for example, amine, known, for example, as Rink amide resin, or an OH group, known, for example, as Wang resin or Kaiser""s oxime resin. Alternatively, other polymeric supports such as glass, cotton, or cellulose having various intermediate chains L can be employed.
The intermediate chain designated by L is covalently bonded to the polymeric support and allows a reversible, amide-like or ester-like bond with the compound of formula IVa, which remains stable during the further reaction on the bonded compound of formula IVa; but under strongly acidic reaction conditions, e.g., mixtures with trifluoroacetic acid, releases the group located on the linker again. The release of the desired compound of formula I from the linker can be carried out at various positions in the reaction sequence.
A. General procedure for the coupling of protected aminocarboxylic acids of formula IVa to the solid support according to process variant b) in the general working procedure:
The synthesis was carried out in reactors each having a reaction volume of 15 ml. Each of the reactors was filled with 0.179 g of Rink amide AM resin (Fmoc-Rink amide AM/Nova-Biochem; loading 0.56 mmol/g; i.e., 0.1 mmol/reactor). For the removal of the Fmoc protective group from the resin, a 30% strength piperidine/DMF solution was metered into each reactor and the mixture was shaken for 45 minutes (min). It was then filtered and the resin was washed three times with dimethylformamide (DMF).
For the coupling of the protected amino acid, a 0.5 molar solution of the corresponding Fmoc-amino acid (0.3 mmol in DMF), a solution of HOBt (0.33 mmol in DMF), and a solution of DIC (0.33 mmol in DMF) were each added to the resin thus prepared and the mixture was shaken at 35xc2x0 C. for 16 hours (h). The resin was then washed with DMF a number of times.
To check the coupling, a few resin beads were removed and subjected to a KAISER test; in all cases the test was negative.
The removal of the Fmoc protective group was carried out, as mentioned above, using 30% strength piperidine/DMF solution.
For the coupling of the benzimidazolecarboxylic acids, a 0.1 molar solution of the corresponding 4- or 5-substituted acid (0.4 mmol in DMF), a 0.5 molar solution of the coupling reagent TOTU (0.44 mmol in DMF), and a 0.5 molar solution of DIPEA (0.6 mmol in DMF) were added and the mixture was shaken at 40xc2x0 C. for 16 h. It was then washed a number of times with DMF.
To check the reaction, a few beads of resin were again removed and subjected to a KAISER test.
For the removal of the desired substances from the solid support, the resin was washed a number of times with dichloromethane. The cleavage solution (50% dichloromethane and 50% of a mixture of 95% TFA, 2% H2O, and 3% triisopropylsilane) was then added and the mixture was shaken at room temperature (RT) for 1 h. The mixture was filtered and the filtrate was concentrated to dryness. The residue was precipitated with diethyl ether and filtered.
The solid residues usually contained the desired products in high purity or were fractionated, for example, on a reverse phase (eluent: A: 100% H2O/0.1 % TFA, B: 100% acetonitrile/0.1% TFA) using preparative high-pressure liquid chromatography. Lyophilization of the fractions obtained yielded the desired products.
The preparation of physiologically tolerable salts of compounds of formula I capable of salt formation, including their stereoisomeric forms, is carried out in a manner known per se. With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides, and also ammonia or organic bases, for example, trimethyl- or triethylamine, ethanolamine, or triethanolamine, or alternatively basic amino acids, for example, lysine, ornithine, or arginine, the carboxylic acids form stable alkali metal, alkaline earth metal, or optionally substituted ammonium salts. If compounds of formula I contain basic groups, stable acid addition salts can also be prepared using strong acids. For this, both inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic, trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic, or trifluoroacetic acid are suitable.
The invention also relates to pharmaceuticals comprising an efficacious amount of at least one compound of formula I or of a physiologically tolerable salt of compounds of formula I or an optionally stereoisomeric form of compounds of formula I, together with a pharmaceutically suitable and physiologically tolerable excipient, additive, and/or other active compounds and auxiliaries.
On account of the pharmacological properties, compounds according to the invention are suitable for the prophylaxis and therapy of all those disorders in whose course an increased activity of IxcexaB kinase is involved. These include, for example, asthma, rheumatoid arthritis (in the case of inflammation), osteoarthritis, Alzheimer""s disease, carcinomatous disorders (potentiation of cytotoxic therapies), cardiac infarct, cardiac insufficiency, acute coronary syndrome (unstable angina pectoris), septic shock, acute and chronic kidney failure, stroke, or atherosclerosis. In both the specification and the amended claims, the term xe2x80x9ctreatingxe2x80x9d includes prophylaxis and/or prevention.
The pharmaceuticals according to the invention are in general administered orally or parenterally. Rectal, inhalative, or transdermal administration is also possible.
The invention also relates to a process for the production of a pharmaceutical, comprising bringing at least one compound of formula I into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives, or auxiliaries.
Suitable solid or pharmaceutical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injectable solutions, and preparations having protracted release of active compound, in whose preparation customary auxiliaries, such as excipients, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners, and solubilizers are used. Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactoprotein, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower, groundnut, or sesame oil, polyethylene glycol, and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.
The pharmaceutical preparations are preferably produced and administered in dose units, each unit containing as active constituent a certain dose of the compound of formula I according to the invention. In the case of solid dose units such as tablets, capsules, coated tablets, or suppositories, this dose can be up to approximately 1000 mg, preferably from approximately 50 mg to 300 mg, and in the case of injection solutions in ampoule form up to approximately 300 mg, preferably from approximately 10 mg to 100 mg.
For the treatment of an adult patient weighing approximately 70 kg, depending on the efficacy of the compound according to formula I, daily doses of approximately 20 mg to 1000 mg of active compound, preferably from approximately 100 mg to 500 mg, are indicated. Under certain circumstances, however, even higher or lower daily doses may be appropriate. The administration of the daily dose can be carried out both by single administration in the form of an individual dose unit or else of a number of smaller dose units and by multiple administration of subdivided doses at specific intervals.
As a rule, final products are determined by mass-spectroscopic methods (FAB-, ESI-MS). Unless stated otherwise, temperatures are given in degrees Celsius and RT means RT (22xc2x0-26xc2x0 C.). Abbreviations used are either explained or correspond to the customary conventions.
Examples according to process variant b) as in the general working procedure
HPLC (RP 18; UV 210 nm): gradient 0-15 min. B=5-70% (A=100% H2O/0.1% trifluoroacetic acid; B=100% acetonitrile/0.1% trifluoroacetic acid)